A pharmacological review of selective oestrogen receptor modulators

Selective oestrogen receptor modulators (SERMs) are structurally diverse non-steroidal compounds that bind to oestrogen receptors and produce oestrogen agonist effects in some tissues and oestrogen antagonist effects in others. SERMs are being evaluated for a number of oestrogen-related diseases, including post-menopausal osteoporosis, hormone-dependent cancers, and cardiovascular disease. Several compounds that exhibit a SERM profile are currently available for clinical use, including clomiphene, tamoxifen, and toremifene (which are triphenylethylenes) and raloxifene (a benzothiophene). Clomiphene is used for the induction of ovulation in sub-fertile women attempting pregnancy. Tamoxifen and toremifene are both used to treat breast cancer. Tamoxifen may have beneficial effects on bone mineral density and serum lipids. The effects of toremifene on serum lipids are similar to that of tamoxifen. Both compounds have stimulatory effects on the endometrium. Raloxifene, indicated for the treatment and prevention of post-menopausal osteoporosis, has beneficial effects on bone mineral density and serum lipids, but does not increase the risk of endometrial hyperplasia or endometrial cancer. Recently, raloxifene was shown to reduce the incidence of vertebral fractures in otherwise healthy women with osteoporosis; in the same study, a reduced incidence of breast cancer was also observed. Similar to oestrogens, SERMs increase the incidence of venous thromboembolism. Several newer compounds that exhibit a SERM profile are also in clinical development, including other triphenylethylenes (droloxifene, idoxifene) and benzothiophenes (LY353381.HCl), benzopyrans (EM-800), and naphthalenes (CP-336,156).     

Selective estrogen receptor modulators (SERMs) and retinoids in breast cancer chemoprevention

Tamoxifen has been shown to decrease the risk of invasive breast cancer by 49% and noninvasive breast cancer by 50%. Tamoxifen is also associated with a threefold increased risk of endometrial cancer. Raloxifene, a second-generation selective estrogen receptor modulator (SERM), has not been associated with endometrial cancer risk, and is currently under study in a large, multi-institutional, randomized Study of Tamoxifen and Raloxifene (STAR) for breast cancer prevention in postmenopausal women. A pilot trial of raloxifene in premenopausal women to assess the safety, tolerability, effects on bone mineral density, mammographic density, and other biological endpoints is ongoing. The retinoids have been shown to decrease mammary tumors in rodent carcinogenesis models. The Italian trial of fenretinide (4-HPR) in women with stage I breast cancer randomized women to fenretinide or no intervention. This study did not show an overall effect of decreasing the risk of contralateral breast cancer. However, a protective effect was suggested in premenopausal women. It has been suggested that this effect may be related to insulin-like growth factor 1 (IGF-1), which has been shown to be modulated by fenretinide in premenopausal but not postmenopausal women. Pilot studies of SERMs alone and in combination with retinoids or other agents provide a model for testing the safety and tolerability, pharmacokinetics and pharmacodynamics, and biomarker modulation in high-risk women. These studies can provide information as to both the pathophysiology of carcinogenesis and the mechanism of action of chemopreventive agents, and help select agents and doses for testing in large randomized studies.     

Selective estrogen receptor modulators: A possible new treatment of osteoporosis in males

More recently, osteoporosis in men has been recognized as an important public health problem. Bone loss begins in mid life and is associated with the decline of the sex steroids production. Although there is no equivalent of the menopause, gonadal function in men is affected in a slow progressive way leading to hypogonadism. Testosterone, the major androgen in men, exerts its effect on bone by local conversion to 5alpha-dihydrotestosterone or by aromatization to estrogens. Several studies have found that estrogen, rather than testosterone, levels are more closely correlated with BMD in elderly men. Selective estrogen receptor modulator (SERM) raloxifene binds to estrogen receptors and exhibit estrogenic effect in bone, but, contrary to estrogen, without feminizing effect. There are limited numbers of studies investigating the effects of SERMs in males. Animal studies demonstrated that SERMs inhibit bone turnover and prevent bone loss in orchidectomised adult male rats. Raloxifene has been shown to increase bone mineral density of the hip in men receiving androgen deprivation therapy for prostate cancer. Moreover, experimental data demonstrated dramatic increase in cell death in human prostate cancer cell lines after the treatment with raloxifene. All these observations suggest that SERMs may be useful for the prevention and treatment of osteoporosis not only in postmenopausal women but also in elderly men. However, our hypothesis should be tested in a proper designed clinical trial. Several important issues have to be addressed. Does the same drug dose that has been shown to be effective in postmenopausal women should be used in men, too? Does treatment with SERMs reduce the fracture risk in men and is it comparable to that observed in women? Does treatment with SERMs have any beneficial effect on cardiovascular system and prostate cancer? And finally, do men experience adverse events other than women treated with SERMs? Answering to these questions will have great impact in getting the decision of possible SERMs usage in the treatment of osteoporosis in elderly males.     

Hormone replacement therapy: the perspectives for the 21st century.

Nowadays different lines of evidence demonstrate the benefits of postmenopausal hormone replacement therapy (HRT). HRT is extremely effective in treating subjective symptoms and can really improve the quality of life of climacteric women. HRT and dementia: Estrogens are potentially relevant to the pathogenesis and treatment of Alzheimer's disease. The effects of different progestogens on cognitive functions and Alzheimer's disease are largely unknown. The prevention of Alzheimer disease might be a major indication to long term HRT. Large prospective, randomized trials will confirm these preliminary data. HRT and osteoporosis: HRT has been strongly correlated with higher bone mineral density and lower fracture incidence. Definite answers in terms of minimum effective dosages, timing and duration of HRT for fracture prevention are needed. HRT and cardiovascular disease: Different lines of evidence suggest that HRT can exert cardioprotective effects with substantial reduction of morbidity and mortality for cardiovascular disease in postmenopausal women. The effects and the role of progestogens in cardiovascular disease prevention are still debated. Prospective, randomized, controlled studies are needed to assess the impact of different HRT regimens on cardiovascular events. HRT and cancer: The major issue in the relationship between HRT and cancer is breast cancer. Long-term and current HRT use are followed by a slight, though significant increase in the risk of breast cancer. Progestogens can modify the cellular response of normal as well as cancer breasts. The possible protective effect of continuous progestogen addition is very interesting and needs further investigation. Alternative to classical HRT: Selective estrogen receptor modulators (SERM). SERMs such as raloxifene (RAL) are a new class of drugs that exert site specific estrogenic or antiestrogenic effects in different target tissues. RAL prevents bone loss and reduces serum cholesterol in postmenopausal women. In contrast to estrogen RAL does not stimulate breast or uterine tissues. In vitro RAL is highly effective at inhibiting the growth of estrogen-dependent breast adenocarcinoma cells. SERMs are expected to represent a major breakthrough for postmenopausal health. CONCLUSION: HRT can be offered either as a preventive tool or as individualized care on the basis of personal needs. New therapeutic options like the SERMs will offer a substantial medical advancement for the treatment of postmenopausal women.     

SERMs: Progress and future perspectives

Selective estrogen receptor modulators (SERMs) interact with estrogen receptors as agonists or antagonists depending on the target tissue. Currently available SERMs are used to treat and prevent breast cancer and osteoporosis, to treat ovulatory dysfunction in women, and for contraception. Because current therapies do not adequately treat menopausal symptoms, the search continues for the optimal SERM for postmenopausal women, which would relieve hot flushes, treat vaginal atrophy, and prevent fractures, while protecting the endometrium, breast, and cardiovascular system. Future use of SERMs may also include their use in a tissue selective estrogen complex (TSEC), a therapy that combines a SERM with estrogen(s), designed to deliver the efficacy of each component with improved overall tolerability for the treatment of postmenopausal women. The future of SERMs may also include their use in men for the treatment of osteoporosis and various syndromes associated with secondary hypogonadism and possibly prostate cancer. Continued research should allow the full potential of SERMs to be uncovered.     

Cognitive function in postmenopausal women treated with raloxifene

BACKGROUND: In postmenopausal women, estrogen may have a beneficial effect on cognition or reduce the risk of decline in cognitive function. Whether raloxifene, a selective estrogen-receptor modulator, might have similar actions is not known. METHODS: As part of the Multiple Outcomes of Raloxifene Evaluation trial, we studied 7478 postmenopausal women with osteoporosis (mean age, 66 years), who were enrolled at 178 sites in 25 countries. The women were randomly assigned to receive raloxifene (60 mg or 120 mg) or placebo daily for three years. We compared the mean scores of the groups on six tests of cognitive function, which were administered at base line and at six months and one, two, and three years. Women were classified as having a decline in cognitive function if the change in their scores at three years was in the worst 10 percent. RESULTS: The mean cognitive scores in the three groups of women were similar at base line. The scores improved slightly in all three groups during the three-year study period, with no significant differences among the groups. The risk of decline in the cognitive function, as measured by four of the six tests, did not differ significantly between the two raloxifene groups combined and the placebo group, but there was a trend toward less decline in the combined raloxifene group on the two tests of verbal memory (relative risk, 0.77) and attention, (relative risk, 0.87). Newly reported or worsening hot flashes did not negatively influence test scores or the effect of treatment on test performance. CONCLUSIONS: Raloxifene treatment for three years does not affect overall cognitive scores in postmenopausal women with osteoporosis.     

Prevention of osteoporosis and uterine effects in postmenopausal women taking raloxifene for 5 years

OBJECTIVE: Raloxifene hydrochloride (60 mg/day) is a selective estrogen receptor modulator indicated for the prevention and treatment of postmenopausal osteoporosis. Raloxifene treatment for 3 years increases bone mineral density (BMD) and, unlike tamoxifen (a triphenylethylene selective estrogen receptor modulator), does not stimulate the endometrium in healthy postmenopausal women. The effect of longer duration of treatment with raloxifene is not known. Therefore, the main objectives of these analyses are (1) to compare the effect of 5 years of treatment with raloxifene (60 mg/day) with placebo in terms of the likelihood of developing osteoporosis and (2) to evaluate the effect of 5 years of raloxifene treatment on the endometrium and incidence of vaginal bleeding. DESIGN: The current analyses include integrated data from two identically designed, prospective, double-blinded trials including postmenopausal women (mean age, 55 years) randomly assigned to either placebo (n = 143) or raloxifene (60 mg/day; n = 185). Osteoporosis and osteopenia were diagnosed according to World Health Organization criteria, using the manufacturer's database for the lumbar spine and the National Health and Nutrition Examination Survey's 1998 reference base for the hip. Endometrial thickness was determined using transvaginal ultrasonography. Clinical diagnoses of endometrial hyperplasia or endometrial cancer were confirmed by blinded review of histopathology reports. RESULTS: Compared with the case of placebo, raloxifene treatment for 5 years reduced bone turnover markers (osteocalcin: -10.9%, P < 0.001; bone-specific alkaline phosphatase: -7.2%, P = 0.042; urinary C-telopeptide: -11.1%, P = 0.034) and was associated with increased BMD in the lumbar spine (2.8%; P < 0.001) and total hip BMD (2.6%; P < 0.001). Women taking raloxifene were less likely to develop osteoporosis (relative risk [RR] for raloxifene v placebo: 0.13; 95% CI: 0.00, 0.37; P = 0.001) or osteopenia (RR: 0.23; 95% CI: 0.00, 0.81; P = 0.038) at the lumbar spine and were more likely to convert to normal BMD status at the lumbar spine (RR: 4.01; 95% CI: 1.34, 11.23; P = 0.043) and total hip (RR: 3.92; 95% CI: 1.12,14.27; P = 0.011) at 5 years, compared with the case of placebo. Raloxifene also significantly reduced total cholesterol (-5.5%; P < 0.001) and low-density lipoprotein cholesterol (-8.7%; P < 0.001), compared with the case of placebo. No significant changes in high-density lipoprotein cholesterol (P = 0.257) or triglycerides (P = 0.620) were detected. Incidence of hot flashes was higher among women taking raloxifene compared with those taking placebo [raloxifene, 47 (28.8%); placebo, 21 (16.8%); P = 0.017]. Women taking placebo or raloxifene reported a similar incidence of vaginal bleeding (P = 0.999) or of mean endometrial thickness of more than 5 mm at baseline and at each visit, up to the 5-year endpoint (P >/= 0.349). No diagnoses of endometrial hyperplasia or endometrial cancer were made in either treatment group. CONCLUSIONS: Five years of raloxifene treatment in healthy postmenopausal women preserves BMD, significantly reduces the likelihood of development of osteoporosis, and was not associated with an increased rate of vaginal bleeding, endometrial hyperplasia, or endometrial carcinoma, compared with the case of placebo.     

Post-menopausal women and osteoporosis: available choices for maintenance of skeletal health

Objective: To briefly summarize the therapeutic choices for osteoporosis prevention which are currently available to post-menopausal women. Methods: Results of randomized clinical trials and epidemiological studies in post-menopausal women, and pre-clinical studies in ovariectomized rats were summarized. Results: Estrogen combined with progestogen in hormone replacement therapy (HRT) is effective in relieving perimenopausal symptoms and maintaining bone mineral density. However, the increased breast cancer risk associated with long-term HRT use makes it a less desirable option for many women. Selective estrogen receptor modulators (SERMs), such as raloxifene, are also effective in maintaining bone density, without stimulating the breast or uterus. However, SERMs do not relieve perimenopausal hot flashes. Conclusion: HRT is effective for acute relief of perimenopausal symptoms, but for women who are unwilling or unable to take HRT long-term, SERMs such as raloxifene are a useful therapy for the prevention of osteoporosis.     

Skeletal effects of selective oestrogen receptor modulators (SERMs)

Women suffer a higher incidence of osteoporosis than men, in part due to oestrogen deficiency after menopause. In fact, the administration of oestrogen to post-menopausal women is associated with a decrease of bone resorption. Tamoxifen is a widely used selective oestrogen receptor modulator in women with breast cancer, which has been shown an agonistic profile in bone. However, tamoxifen seems less effective than oestradiol as an anti-resorptive agent and has no effect when the endogenous production of oestrogen is normal. Additionally, tamoxifen exhibits agonistic activity on the endometrium and has been suggested an oncogenic potential on that tissue. Raloxifene, a selective oestrogen receptor modulator from the benzothiophene family, behaves also as an agonist on the bone in both laboratory and clinical studies. Ongoing clinical trials confirm a protective effect of raloxifene similar to oestrogens. The Multiple Outcome of Raloxifene Evaluation (MORE) study is a prospective, randomized trial which, in a recent 2 year interim analysis, has shown that women suffering from osteoporosis receiving raloxifene had 42% fewer vertebral fractures than women receiving a placebo.     

Endometrial response to raloxifene compared with placebo, cyclical hormone replacement therapy, and unopposed estrogen in postmenopausal women.

OBJECTIVE: To determine the endometrial effects of raloxifene 60 mg/day in postmenopausal women as assessed by vaginal bleeding and endometrial thickness. DESIGN: Data from 1157 postmenopausal women were analyzed from a database consisting of four independent, double-blind, randomized, placebo-controlled trials (range = 6-30 months duration), a 24-month open-label randomized, cyclical hormone replacement therapy (HRT)-controlled trial, and a 6-month double-blind, randomized, unopposed estrogen-controlled trial. Vaginal bleeding rate was derived from self-reported adverse events collected at least every 6 months. Endometrial thickness was measured by ultrasonography at regular intervals. RESULTS: Raloxifene 60 mg/day was not significantly different from placebo with regard to the incidence of vaginal bleeding, the baseline-to-endpoint change in endometrial thickness, or the proportion of women experiencing an increase in endometrial thickness above baseline after either 12 or 24 months of therapy. Unexpected bleeding was reported significantly more frequently in the unopposed estrogen groups compared with the raloxifene group (raloxifene 60 mg/day, 0% versus estrogen, 50%; p = 0.002). A significantly greater baseline-to-endpoint increase in endometrial thickness was observed in both the HRT and estrogen groups compared with their respective raloxifene comparison group (raloxifene 60 mg/day, 0.01 +/- 2.0 mm versus HRT, 1.8 +/- 3.2; p < 0.001; raloxifene 60 mg/day, 1.1 +/- 1.7 mm versus estrogen, 7.8 +/- 3.8; p < 0.001). No cases of endometrial hyperplasia or cancer were diagnosed in the placebo or raloxifene 60 mg/day groups. Endometrial hyperplasia was diagnosed in one case in the HRT group and in two cases in the estrogen group. CONCLUSION: Raloxifene 60 mg/day for up to 30 months is not associated with vaginal bleeding or increased endometrial thickness in postmenopausal women.     

Cognitive changes associated with endocrine therapy for breast cancer

Endocrine therapy in the setting of breast cancer has undoubtedly advanced clinical outcomes in this disease, but treatment with endocrine therapy is accompanied by a wide spectrum of side effects. It is of prime importance to understand and characterize these toxicities to facilitate clinical decision-making. Somewhat surprisingly, there is a relative paucity of data pertaining to cognitive changes associated with endocrine therapy. In this article we review cognitive associated with two classes of endocrine therapy: (1) selective estrogen receptor modulators (SERMs; tamoxifen and raloxifene) and (2) aromatase inhibitors (AIs; anastrozole, letrozole, and exemestane). Companion studies to the Multiple Outcome of Raloxifene Evaluation (MORE), the Study of Tamoxifen and Raloxifene (STAR) and National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trials provide relevant data to understand the effect of SERMs on cognition. In contrast, substudies of the Arimidex, Tamoxifen Alone or in Combination (ATAC), Tamoxifen and Exemestane Adjuvant Multinational (TEAM) and Breast International Group (BIG) 1-98 trials juxtapose cognitive effects of AIs against those of tamoxifen. These and other studies are examined herein to provide a comprehensive overview of the effect of endocrine therapy on cognition.     

Mood effect of raloxifene in postmenopausal women

OBJECTIVE: Some experimental and observational data suggest a role of estrogen in depression. Raloxifene is a selective estrogen receptor modulator (SERM) approved for the prevention and treatment of postmenopausal osteoporosis. Its influence on mood in postmenopausal women has not been fully established. Thus, we investigated the effect of raloxifene on mood. METHODS: In a randomized double-blind osteoporosis prevention study, the action of raloxifene on mood was assessed in a subgroup of non-depressed postmenopausal women (mean age: 58.9 years) receiving raloxifene 60 mg/day (n=18) or placebo (n=18). The Hamilton Depression Rating Scale (HDRS) was applied to evaluate mood 3 and 12 months following treatment. RESULTS: Baseline HDRS scores were not different among treatment groups. Overall scores decreased from baseline at 3 and 12 months in the raloxifene group (P相似文献   

Characterization of hot flashes reported by healthy postmenopausal women receiving raloxifene or placebo during osteoporosis prevention trials

OBJECTIVE: Raloxifene, a selective estrogen receptor modulator, is estrogen-like in the skeleton and cardiovascular system and antiestrogenic in reproductive tissues. In contrast to estrogens, raloxifene is not indicated for the treatment of hot flashes. This study was designed to examine the characteristics of hot flashes among healthy postmenopausal women participating in osteoporosis prevention trials who were receiving raloxifene or placebo. METHODS: Adverse event data from three randomized, double-blind trials (N = 876) comparing raloxifene 60 mg/day with placebo for 30 months were integrated and analyzed. Two of the three trials (one European, two North American) were identically designed and were open to healthy postmenopausal women ages 45 through 60 without regard to prior hysterectomy. The third trial was multinational, was open to women ages 40 through 60, and all enrollees had prior hysterectomy at baseline. Women were questioned in general terms about the occurrence of adverse events at 3-6-month intervals. Treatment-emergent adverse events pertaining to hot flashes were included in the current study. RESULTS: At baseline, 12% of women randomly assigned to placebo and 13% assigned to raloxifene reported prevalent hot flashes. After 30 months, the cumulative incidence of hot flashes was 21% for placebo and 28% for raloxifene (P = 0.022), with the difference in incidence rate confined to the first 6 months of therapy. There was no difference between placebo and raloxifene in reported maximum severity of or early discontinuations as a result of hot flashes (< or = 3% per group for both outcomes). Among women whose hot flashes had stopped completely during the 30-month study period, the median total duration of the event prior to becoming symptom-free was 246 days for placebo and 205 days for raloxifene. Among all women reporting a hot flash, the extrapolated total duration of hot flashes was the same for women treated with either raloxifene or placebo. No subgroup-by-therapy interactions were detected. Multivariable regression analysis revealed several factors that were independently weakly predictive of hot flashes. CONCLUSIONS: Raloxifene slightly affects the incidence but not the natural history of hot flashes in healthy postmenopausal women seeking prevention therapy.     

Raloxifene lowers serum lipoprotein(A) in healthy postmenopausal women: a randomized, double-blind, placebo-controlled comparison with conjugated equine estrogens.

OBJECTIVE: Long-term postmenopausal estrogen replacement therapy lowers the risk of osteoporotic fractures and coronary artery disease but increases the risk of endometrial cancer and probably breast cancer. Raloxifene, a nonsteroidal estrogen receptor ligand, seems to have a tissue-specific antiestrogenic action on endometrium and breast and the desired estrogenic action on bone and lipid metabolism. The purpose of this study was to investigate the effects of 24-month treatment with orally administered raloxifene in two doses (60 mg and 150 mg daily) and conjugated equine estrogens in a standard oral dose (0.625 mg daily) on serum lipoprotein(a) [Lp(a)], an independent risk factor for coronary artery disease, in healthy postmenopausal women who had undergone hysterectomy. DESIGN: A randomized, double-blind, placebo-controlled study was performed with 56 women. RESULTS: In the placebo group serum Lp(a) levels did not change throughout the study. After 6 months, serum Lp(a) was significantly reduced versus baseline in the raloxifene 150 (-17%; p = 0.003) and conjugated equine estrogens (-26%; p = 0.003) groups, but this reduction was significantly different from placebo only in the conjugated equine estrogens group. At 12 and 24 months, serum Lp(a) levels were significantly lowered versus baseline in all active treatment groups. However, these reductions were significantly different from placebo only in the raloxifene 150 and conjugated equine estrogens groups. After 24 months, serum Lp(a) was reduced versus baseline with 30% (p = 0.001) in the raloxifene 150 group and 35% (p = 0.001) in the conjugated equine estrogens group. CONCLUSIONS: Long term raloxifene treatment significantly lowers serum Lp(a) levels in postmenopausal women and thus might reduce the risk of coronary artery disease.     

Use of FRAX®-based fracture risk assessments to identify patients who will benefit from osteoporosis therapy

Several pharmacological interventions, including selective estrogen receptor modulators (SERMs), bisphosphonates, denosumab, and strontium ranelate have demonstrated efficacy in reducing the incidence of osteoporotic fractures, the most severe consequence of postmenopausal osteoporosis. Until recently, bone mineral density (BMD) was the primary factor used to determine which postmenopausal women may require osteoporosis treatment. However, clinical guidelines now recommend the use of the Fracture Risk Assessment Tool (FRAX^®), a computer-based algorithm introduced by the World Health Organization, to help primary care physicians identify postmenopausal women who may be candidates for pharmacological osteoporosis therapy based on the level of fracture risk. Beyond its utility as a resource for determining whether or not to initiate osteoporosis treatment, clinical studies have begun to evaluate the correlation between FRAX^®-based 10-year fracture probability and efficacy of different osteoporosis treatments. Bazedoxifene, clodronate, and denosumab have shown greater fracture risk reduction at higher FRAX^®-based 10-year fracture probabilities, but the efficacy of raloxifene, alendronate, and strontium ranelate were relatively stable regardless of fracture probability. In summary, these data suggest that the relationship between FRAX^®-based fracture probability and efficacy of different osteoporosis treatments varies depending upon the agent in question.     

Mammographic changes associated with raloxifene and tibolone therapy in postmenopausal women: a prospective study

OBJECTIVE: The prolonged use of estrogen therapy is associated with a slightly increased risk of breast cancer. Alternative therapies that are effective in the prevention of menopause, having associated morbidities but no unwanted effects, are of primary interest in the pharmacologic research. The aim of this study was to evaluate the effect of two alternative to estrogens drugs, the selective estrogen receptor modulator raloxifene and the tissue-specific tibolone, on the mammographic appearance of the breast. DESIGN: The study group comprised 131 postmenopausal women aged 41 to 67 years. The women were at least 2 years postmenopausal, free of climacteric symptoms, and at the time of entry to the study had not had therapy for at least 9 months. Women with risk factors for osteoporosis or cardiovascular disease were allocated either to tibolone (n = 56) or raloxifene (n = 48) therapy. Women with no risk factors and women who either did not qualify for or denied treatment (n = 27) served as controls. The study duration was 12 months. Women received a baseline mammogram before commencing therapy and a repeat mammogram at the end of the study period. Mammogram findings were classified according to the modified Wolfe criteria by two expert radiologists. RESULTS: No difference was identified between groups with respect to baseline characteristics associated with breast cancer risk. Similarly, no difference was detected between groups concerning the modified Wolfe classification of baseline mammographic findings. In the tibolone group, 10.7% of the women showed an increase in breast density in the 12-month reevaluation. The respective figure in the raloxifene group was 6.3%, whereas no woman in the control group showed an increase in breast density. Differences in the increase in breast density between groups did not, however, reach statistical significance. Accordingly, 10.7% of women in the tibolone group and 18.8% of women in the raloxifene group exhibited involutionary changes in the repeat mammogram, whereas 25.9% of women in the control group revealed a decrease in breast density in the 12-month examination. The percentages were not significantly different between groups. CONCLUSIONS: Breast density as shown by mammography was stable in a majority of patients and changed in a minority of cases for both tibolone and raloxifene. In most patients, these drugs are not likely to interfere with mammogram interpretation. Larger long-term studies are needed to confirm the impact of prolonged tibolone or raloxifene administration on mammography.     

Progress in endocrine approaches to the treatment and prevention of breast cancer

Tamoxifen had been the only available hormonal option for the systemic treatment for breast cancer from 1973 to 2000. Enormous efforts have led to the development of potent and selective third generation aromatase inhibitors including anastrozole, letrozole and exemestane. Due to their superior efficacy to tamoxifen, aromatase inhibitors are presently approved as first line agents for the treatment of advanced estrogen receptor (ER) positive breast cancer and adjuvant therapy in early ER positive early breast cancer in postmenopausal women. Selective ER Modulators (SERMS), tamoxifen and raloxifene are the only agents presently used in breast cancer prevention in high risk women and their use has increased substantially over the last decade. Third generations SERMS, lasofoxifene and bazedoxifene have shown significant reduction in bone loss compared to placebo in postmenopausal women and are currently approved in the European Union for the treatment of postmenopausal osteoporosis. This review outlines the current strategies employed in the use of endocrine therapy in the management and prevention of breast cancer.     

Prevention of postmenopausal osteoporosis with oestrogen replacement therapy and associated compounds: update on clinical trials since 1995

Hormonal replacement therapy (HRT) is generally regarded as first choice for pharmacological prevention of osteoporosis in women. We reviewed recent studies of HRT regimens and selective oestrogen receptor modulators (SERMs), including controlled trials of at least one-year duration published since 1995 until February 2000 providing data on bone mineral density (BMD) or fractures. Natural and synthetic oestrogens exert a continuum of positive effects on BMD in a dose-dependent, though non-proportional, fashion independent of age and mode of administration. Bone loss may be largely prevented by 25 microg transdermal patch oestradiol, 0.3 mg conjugated equine or 0.3 mg esterified oestrogens. Progestogens neither attenuate nor augment the effect of oestrogens; sole use of tibolone prevents bone loss. Both the SERMs, tamoxifen and raloxifene, slightly increase BMD. There are no adequately powered fracture trials for any HRT regimen. Raloxifene 60 mg daily decreases the relative risk of vertebral fractures by at least 30%, as demonstrated by one 3-year fracture study of osteoporotic women. In conclusion, the recommendation to use oestrogen for postmenopausal osteoporosis, given both the lack of fracture trials and the rare trials on long-term use of HRT in (late) postmenopausal women, is not well supported. Fracture trials could overcome shortcomings of the current level of evidence.     

Ospemifene,vulvovaginal atrophy,and breast cancer

The incidence and severity of vulvovaginal atrophy (VVA) in postmenopausal breast cancer patients has a significant impact on quality of life. While the etiology of VVA is primarily related to low estrogen levels seen in menopause, women with breast cancer have an added risk of VVA induced by a combination of chemotherapy, hormonal therapy, and menopause. Ospemifene is a new, non-hormonal selective estrogen receptor modulator (SERM) triphenylethylene derivative that is effective in treating VVA in postmenopausal women. Although other SERMs have antagonistic effects on the vagina, ospemifene exerts an estrogen-like effect on the vaginal epithelium. This review will focus on data demonstrating the antiestrogenic activity of ospemifene in several unique breast cancer animal models, and the implications for utilizing ospemifene in patients with breast cancer suffering from VVA. Additional research addressing the expanded use of ospemifene in breast cancer patients is also warranted.     

Estradiol,but not raloxifene,improves aspects of spatial working memory in aged ovariectomized rhesus monkeys

Estrogen replacement therapy (ERT) alleviates many postmenopausal symptoms but whether it also benefits cognitive function remains controversial. Further, since estrogen increases the risk of breast and uterine cancers, a new class of compounds, called selective estrogen receptor modulators (SERMs) is being considered as possible alternative to ERT. The SERM raloxifene is particularly interesting because, like estrogen, it improves lipid metabolism and reduces bone loss, without adverse effects on the breast or uterus. Little is known, however, about its effect upon cognitive function.We used a rhesus monkey model of human menopause to examine the effects of ERT and raloxifene on cognitive function. We tested 5 aged females (21-24 years old) ovariectomized long-term (10-16 years) on a battery of age-sensitive tasks, including the Delayed Response (DR), the Delayed Non-Matching-to-Sample-10 min (DNMS-10 min) and the spatial-Delayed Recognition Span Test (DRST). Monkeys were tested 5 days a week on each task for 9 consecutive months, while undergoing treatments with placebo, ethinyl estradiol (EE(2)), and raloxifene in alternating 28-days blocks. EE(2) transiently enhanced the working memory component of the spatial-DRST, but did not affect performance on the other tasks of the battery. Raloxifene had no effect on cognitive performance. These findings indicate that estradiol is able to enhance some aspects of spatial working memory in aged monkeys despite many years of estrogenic deprivation. Further, they suggest that raloxifene does not affect cognitive function after long-term ovarian hormone deprivation.